Current anticancer agents continue to face substantial challenges, including inherently narrow therapeutic indexes (TIs) as well as suboptimal therapeutic combinations, stemming from mixtures of active pharmaceutical ingredients (APIs) with dissimilar properties. While nanomedicine-based platforms for drug delivery can potentially address these challenges, key questions remain, including “do synergistic free drug ratios translate to nanocarriers?” and “are nanocarriers with multiple drugs better than mixtures of single-drug nanocarriers at the same dose?”. Here, we report a prodrug platform that allows us to answer these questions in the context of advanced clinical therapies for relapsed multiple myeloma (MM), including bortezomib-based (Btz) monotherapy and combination therapies with Btz, pomalidomide (Pom), and dexamethasone (Dex). For Btz monotherapy, a Btz-“bottlebrush prodrug” (BPD) is designed that enables a 25-fold increase in API dosing when compared to Btz alone and without observable toxicities in mice. Moreover, Btz-BPD significantly slows tumor progression in vivo, providing marked enhancements in survival in subcutaneous and orthotopic models of MM. In the context of combination therapy, BPDs carrying Btz, Pom, and Dex exhibit in vitro synergistic, additive, or antagonistic patterns that are distinct from the free drug counterparts, which is a perhaps expected, yet undemonstrated, phenomenon. Moreover, a BPD carrying all 3 drugs in a synergistic ratio outperforms the free drug combination, mixtures of single-drug BPDs in the same ratio, as well as an antagonistic 3-drug BPD. Together, our results address unanswered questions in the field of combination nanomedicine, establishing a proof-of-concept for macromolecular prodrug-based approaches that are enabled by the unique BPD architecture in order to potentially improve current front-line mono- and combination therapies.

A convergent platform for translating synergistic drug combinations to nanomedicines: Application to multiple myeloma therapy

ACS Fall 2021

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.